Psychopharmacology Awards – Winners’ Short Orals

This session, in which winners of the Psychopharmacology Awards present their work, always has high attendance and this year was no exception.

Dr Tom Freeman, the winner of the junior non-clinical award, presented on the role of cannabinoids in the development and treatment of addiction. He noted that recent policy changes in the UK have led to cannabinoids being moved to Schedule 2 (from Schedule 1), allowing them to be prescribed in a limited way. Whilst there is much discussion about the harms of cannabis, particularly relating to psychosis, there is a major clinical need which is given less attention – treating addiction to cannabis. He showed data indicating that those requiring treatment for cannabis addiction has increased in the last ten years. Current treatments have limited success, and in particular there is no approved pharmacological agent for cannabis addiction. Dr Freeman then presented data showing that THC (tetrahydrocannabidinol, the intoxicating, cognition-impairing ingredient in cannabis) has increased in a linear fashion over the last ten years, and cannabis resin has also increased in levels of THC.

He subsequently presented data from Utrecht, which has high-quality drug monitoring (due to the fact that coffee shops can be randomly sampled, rather than relying on drug samples seized by policy). This data shows a different pattern, with an increase in THC from 2000-2004, then a decrease. This is followed (with a five-year lag) in increased cannabis addiction treatment entry.

The other active ingredient in cannabis, cannabidiol (CBD) has a contrasting mechanism. It is able to reduce tobacco smoking, and may protect against harms from THC. Dr Freeman and his colleagues subsequently ran a clinical trial of CBD for cannabis addiction, using an adaptive Bayesian dose-finding design (due to lack of knowledge about dose-response effects relationship). In this trial, individuals who had DSM-5 diagnoses of cannabis use disorder and wanted to quit were randomised to placebo or different doses of CBD, and given a 24 week follow-up. Analyses looked at the probability that CBD is the most effective dose compared to placebo, and an intention to treat analysis was used, adjusted for week 0. 400mg doses were effective, and reduced cannabis levels found in urine 45% compared to placebo. A similar, but slightly weaker, pattern was seen for 800mg. This effect was also seen in the other co-primary outcome, abstinence days.

Dr Maddy King received the senior non-clinical award, and discussed her animal work on schizophrenia. She began by motivating her interest in this disorder – whilst schizophrenia is less prevalent than some other disorders, it has a disproportionate impact on quality of life, as shown by DALYs. Schizophrenia is known to have a complex aetiology – with genetic, neonatal, and environmental components. Her work has modelled schizophrenia preclinically in rodents.

One common model is post-weaning social isolation, which results in cognitive deficits and structural/neurochemical changes. However, this model also shows some important differences to schizophrenia – the effects are strain-dependent, and the animals show increased aggression, which is not found in human schizophrenia. Therefore her lab has worked on developing dual-hit models of schizophrenia. The first dual-hit model discussed involves PCP administration pre-weaning, followed by the same social isolation as in the single model. This model exacerbates effects seen in the isolation-only model on water maze reversal learning deficits, pre-pulse inhibition and conditioned freezing. This also leads to relevant neurochemical changes. They used this model to investigate cariprazine: a D3-preferring D3/D2 receptor partial agonist. They found that this drug reverses some of the changes, in particular the locomotor and cognitive ones, but not all of them (in particular, it did not alter the social or fear conditioning deficits). They also tested a 5-HT-6 antagonist, which did not reverse the cognitive effects in this model.

Another dual-hit model they investigated was a combination of maternal administration (maternal day 15) of viral mimetic poly(I:C) followed by social isolation. This caused inflammatory effects and sickness behaviour, but had no effect on litter size or pup weight at weaning. The results were opposite to hypothesised, in that the viral mimetic poly (I:C) administration seemed to protect against isolation-induced changes, both behaviourally and physiologically. These two models can therefore be used to examine risk and resilience. Other work using dual-hit models, however, does not show a clear pattern on which combinations of ‘hits’ cause risk vs. resilience.

Dr King concluded by noting that a potential mechanism for future investigation is changes in the gut microbiome, which occurs in schizophrenia and in some animal models. This could be researched in these dual-hit models. Additionally, dual-hit models which are resilient seem to have higher hippocampus oxytocin levels, which could be a potential target to prevent the onset of isolation syndrome.

Dr Toby Pillinger won the junior clinical award, and presented his work in a talk entitled ‘Don’t go breaking my heart: examining intrinsic and extrinsic cardiometabolic risk in schizophrenia’. He began by noting that much excess mortality in schizophrenia is linked to cardiovascular disease, and that whilst metabolic alterations are often blamed on antipsychotics they may in fact precede them. Meta-analysis work indicates that glucose and lipid dysregulation and immune alterations exist during first episode/onset of psychosis. These types of metabolic differences don’t have different effect sizes, indicating that schizophrenia may be a multisystem disorder.

He wanted to investigate whether antipsychotics themselves are cardiotoxic. Notably, other work has shown that alterations in dopamine can cause cardiotoxicity, and some work has shown that clozapine can increase cardiac fibrosis, inflammation and oxidative stress. There is relatively little human work, however, looking at cardiac function in schizophrenia, and existing work does not use cardiac MRI (the gold standard for investigating this question), or necessarily have groups which are well-matched for other cardiac-related variables. Using cardiac MRI, you can measure the recoil of the heart muscle. T1 relaxation time is prolonged by extra water, which may indicate inflammation, or collagen, which may indicate fibrosis. Patients taking antipsychotics showed prolonged T1 relaxation, which provides evidence for diffuse fibro-inflammatory effects in schizophrenia patients taking antipsychotics not fully explained by classical risk factors.

Some network meta-analytic and meta-regression work was used to answer subsequent questions: can we define the metabolic profiles linked to different antipsychotics, can we predict who will develop metabolic dysregulation with antipsychotics, and is there a link between metabolic dysregulation and psychophathology? Network meta-analysis showed that clozapine and olanzapine are generally worst, increasing BMI, triglycerides and cholesterol, with magnitudes relating to sizeable changes in cardiovascular risk factors. Aripiprazole, brexpiprazole, cariprazine and luradisone are linked to best metabolic outcomes. However, how does this link to the fact that individuals with schizophrenia who are treated with antipsychotics live longer? It seems, in relation to this, that clinical improvement is correlated with the development of metabolic side effects. Those who are older, male, and overweight are more likely to see glucose alterations, and those who are younger are more likely to experience cholesterol changes.

The final award winner was Dr Sameer Jauhar, who won the senior clinical prize. He briefly summarised the dopamine hypothesis, and the potential that the presynaptic dopamine system is altered in psychosis. He reported onw ork showing that baseline dopamine synthesis capacity was associated with antipsychotic response – elevated DSC responded better to antipsychotics from illness onset. However, antipsychotics do not seem to alter DSC, although this is in a small sample size and using ecological treatment with a variety of agents. This may be a possible mechanism for relapse when antipsychotics are stopped.

He then discussed the transdiagnostic dopamine hypothesis, linking schizophrenia and bipolar (with psychosis). His research has shown that DSC is even more elevated in those with bipolar disorder than those with psychosis, and that DSC is related to transdiagnostic positive symptoms (i.e., regardless of diagnosis, greater positive symptoms relate to higher DSC). However, the contribution of mania to dopamine dysregulation is unclear at this point. There is also an inverse correlation between prefrontal (ACC) glutamate and striatal DSC. Work in health controls has shown that apomorphine is able to modulate DSC, with a relationship between baseline and change, which replicated in another dataset (to control for regression to the mean). His twitter summary of this work also links to the papers: https://twitter.com/sameerjauhar/status/1151046626288574464?s=20 (very helpful!).

Overall, a wonderful session, with a great deal of careful, theoretical psychopharmacology research which has greatly contributed to our understanding of psychosis, and may lead to clinical impact in treating cannabis addiction. Congratulations again to all prize winners!

BAP2019TuesAMC16-02

Leave a Reply

Your email address will not be published. Required fields are marked *